1. Field of the Invention
The present invention relates to small molecules that are potent inhibitors of αLβ2 mediated cell adhesion which could be useful for the treatment of inflammatory diseases.
2. Description of Related Art
The integrin family of proteins are heterodimeric receptors which are expressed on all cell types to mediate cell to cell binding and adhesion to extracellular matrix. The β2 (CD18) integrin subfamily is comprised of 3 members, αLβ2 integrin (LFA-1, CD11a/CD18), αMβ2 integrin (Mac-1, CD11b/CD18), and gp 150 β2 integrin (αXβ2 integrin, CD11c/CD18) that are primarily expressed on leukocytes (Sanchez-Madrid et al., J. Exp. Med., 158, 1785-1803 (1983)). αLβ2 integrin is found mostly on T and B lymphocytes, while αMβ2 integrin is present on activated neutrophils, NK cells and some myeloid cells. The αLβ2 integrin binds intracellular adhesion molecules ICAM-1, 2 and 3 found on multiple cell types such as vascular endothelial cells, dendritic cells, epithelial cells, macrophage and T lymphoblasts (Dustin et al., J. Immunology, 137, 245-254 (1986)). Recently there has been evidence presented that αLβ2 integrin binds to ICAM-4 and a novel ligand expressed in brain telencephalin. It has been shown that the I domain of the alpha chain is the major recognition site for its ligands.
αLβ2 integrin adhesion to ICAM-1 is necessary for immune responsiveness of T-lymphocytes to antigens, lymphocyte homing and circulation, and cell emigration to sites of inflammation (Springer, Ann. Rev. Physiol., 57, 827 (1995)). A dominant role of αLβ2 integrin in mediating inflammatory events is shown in several different animal models of inflammatory diseases in which antibodies to αLβ2 integrin or ICAM-1 significantly inhibit development of therapeutic end points (Rothlein et al., Kidney International, 41, 617 (1992); Iigo et al., J. Immunology, 147, 4167 (1991); Bennet et al., J. Pharmacol. and Exp. Therapeutics, 280, 988 (1997)).
Also, β2 integrin subfamily are thought to play a critical role in several types of inflammatory disease processes by interacting with ICAMs. Support for the importance of β2 integrin in mediating inflammatory responses has been demonstrated by the evidence that transendothelial migration in vitro is markedly inhibited by monoclonal antibodies against β2 integrin or ICAM-1 (Smith, Can. J. Physiol. Pharmacol., 71, 76 (1993). Furthermore, blockade of αLβ2 integrin has been shown to inhibit neutrophil influx in almost every system, including skin, peritoneum, synovium, lung, kidney, and heart. As one of the primary ligands for the β2 integrin, it would also be expected that blockade of ICAM-1 would inhibit the inflammatory response (Albelda et al., The FASEB Journal, 8, 504 (1994)).
Moreover, it has been shown that antibodies against αLβ2 integrin suppress rejection after transplantation. WO 94/04188 discloses the use of monoclonal antibodies directed against αLβ2 integrin for all transplantation's, including graft vs. host or host vs. graft diseases.